System and method for intranasal administration of lorazepam

ABSTRACT

A therapeutic composition of lorazepam and its pharmaceutically acceptable derivatives are provided for intranasal administration of at least one predetermined volumetric unit dose in the form of a spray by means that delivers one or more therapeutically prescribed unit doses that are highly accurate as to the volume discharged and which leave no significant quantity of the composition in the delivery means.

FIELD OF THE INVENTION

The invention relates to pharmaceutical drug compositions andpreparations of lorazepam. This invention also relates to pharmaceuticaldrug delivery devices, specifically to devices for the intranasaladministration of lorazepam.

BACKGROUND OF THE INVENTION

Lorazepam preparations for the treatment of anxiety-related disordersand to induce sedation have been previously approved by the U.S. Foodand Drug Administration (“FDA”) and have been long-used for oral,intra-muscular and/or intravenous administration. Lorazepam is currentlymarketed in injectable and tablet formulations. Marketers of thesepreparations have not sought regulatory approval from the FDA for liquidcompositions of the same therapeutic compound for intranasaladministration. This is surprising since it is well-known from theliterature that the intranasal administration of a pharmacologicallyactive compound generally results in a more rapid bioavailability of thecompound, or of its desired active metabolite than if the compound isadministered orally. Moreover, the time required to achieve the sameconcentration of the active compound in the bloodstream e.g., within aperiod of about thirty minutes after administration, is generally lessvia the intranasal route compared to oral administration.

It has been reported that, following oral administration, peak plasmaconcentrations of approximately 25 ng/mL were not observed untilapproximately 2.4 hours after administration with a bioavailability of99.8%. (Greenblat, et al., Journal of Pharmaceutical Sciences, Vol. 66,No. 1 (1979).) It has also been reported that, following intranasaladministration of lorazepam in a Cremophor EL, a non-aqueous vehicle,the time to peak plasma concentration was 1.4 hours with abioavailability of 51%. (Lau and Slattery, International Journal ofPharmaceuticals, 54 (1989) 171-174.)

The intranasal route of administration also provides numerous advantagesover intravenous (IV) and intramuscular (IM) injections. One principaladvantage of intranasal administration is convenience. An injectablesystem requires sterilization of the hypodermic syringe and in theinstitutional setting, leads to concerns among medical personnel aboutthe risk of contracting disease if the they are accidentally stuck by acontaminated needle. Strict requirements for the safe disposal of theused needle and syringe must also be imposed in the institutionalsetting. In contrast, intranasal administration requires little time onthe part of the patient and the attending medical personnel, and is farless burdensome on the institution than injectables. There is nosignificant risk of infection of medical personnel or others in theinstitutional setting that is associated with nasal spray devices.

A second important advantage of intranasal administration over IM and IVis patient acceptance of the drug delivery system. Many, if not most,patients experience anxiety and exhibit symptoms of stress when facedwith hypodermic injections via the IM or IV routes. In some cases, theafter-effects of the injection include burning, edema, swelling,turgidity, hardness and soreness. In contrast, intranasal administrationis perceived as non-invasive, is not accompanied by pain, has nosignificant after-effects and produces the gratification of promptrelief in the patient exhibiting the symptom. This is of particularadvantage when the patient is a child. Most people have some familiaritywith nasal sprays in the form of over-the-counter decongestants foralleviating the symptoms of colds and allergies that they or a familymember have used routinely. Another important consideration is that thepatient can self-administer the prescribed dosage(s) of nasal spray. Anempty nasal spray device, or one containing a non-medicated solution canbe given to the patient to practice the technique for proper insertion,inhalation and activation for self-administration.

In view of the aforementioned advantages and benefits afforded by theintranasal administration, it would be expected that a preparation oflorazepam exhibiting systemic pharmacological activity would presentlybe available for intranasal administration. This has not occurred,despite the fact that preparations for oral, IM and IV administrationhave been approved for commercial use for many years.

Despite the remarkable commercial success that has been enjoyed by thosedrugs that have been made available in intranasal form, in fact, only avery limited number of compounds are commercially available tophysicians to prescribe and dispense to their patients in that form.

Furthermore, only one multiple-dose spray device has apparently beenapproved by the FDA for intranasal administration of an opiate solutionthat is categorized as a controlled substance. The devices that arepresently available exhibit several deficiencies. One spray deviceintended for multiple uses must be primed before use by expelling aportion of the liquid contents in order to assure that the pumpmechanism and delivery tube are filled. Up to seven or eight activationsare required to prime the device. It is also indicated that furtherpriming to disperse one or two sprays is to be performed if the deviceis not used for 48 hours or longer. These procedures necessarily resultin the dispenser being overfilled in order to assure that there will besufficient liquid to deliver the labelled number of doses. It has beenfound that a substantial volume of the controlled substance oftenremains in the device, even after the labelled number of doses have beenadministered. In practice, it has also been found that medical personneland workers at health care facilities routinely abscond with thedispensers, sometimes after the patient has had only one or a few of theprescribed doses in a multi-dose container. This improper use ofcontrolled substances as so-called “recreational drugs” is well-knownamong medical facility managers and law enforcement authorities. So faras is presently known, no preventative measures have been reported thatare effective in dealing with this problem.

A further problem resides in dispensing to a patient intranasal spraydevices with sufficient fluid contents for numerous doses for anxietycontrol purposes. Because a patient suffering from a disorder andexhibiting anxiety may not act rationally in self-administering a drugfor relief of the symptom, there is a potential for overdosing.Moreover, because of the nature and construction of these multiple dosespray devices, medical personnel cannot easily determine the number ofdoses that have been administered by a simple visual inspection of thedevice.

Another problem that has recently been identified in clinical studies isthe relative inaccuracy of multi-dose intranasal delivery devices thatare currently being marketed with opiate solutions for the control ofpain. Not only does the average volume of liquid spray actuallyadministered fall about 10% below the purported dosage appearing on theapproved label for one such product, significant variations were alsoobserved among a series of administrations by each patient in the studygroup. Thus, spray devices tested containing an opiate compound classedas a “controlled substance” by the FDA were found to be capable ofadministering only about 90% by volume of the prescribed dosage, onaverage, and the dosage actually received by each patient in repeatedadministrations exhibited substantial significant variations of from 60%to 130% of the claimed label dosage.

OBJECTS OF THE INVENTION

Accordingly, it is a principal object of the invention to provide anovel therapeutic composition of lorazepam and its pharmaceutical byacceptable derivatives for intranasal administration of at least onepredetermined volumetric unit dose in the form of a spray by means thatdelivers one or more therapeutically prescribed unit doses that arehighly accurate as to the volume discharged and which leave nosignificant quantity of the composition in the delivery means.

Another object of the invention is to provide a novel compositioncomprising lorazepam, a known compound that is approved for oral, IMand/or IV administration, for use in a highly accurate and reproducibleintranasal spray delivery system in a single unit-dose ortherapeutically prescribed multiple unit-dose.

It is a further object of this invention to provide an improvedintranasal dosage composition and method of administration of lorazepamthat exhibits a relatively rapid onset, moderate duration of therapeuticactivity, minimal side effects, improved bioavailability, ease andsafety of administration, and minimal physical discomfort and anxiety tothe patient occasioned by administration.

It is another object of this invention to provide an intranasal deliverysystem for one or more unit doses of novel therapeutic compositionscontaining lorazepam that permits administration of one or moretherapeutically prescribed unit-doses in a medical care facility, suchas a hospital, day clinic, or doctor or dentist's office in which thedelivery system contains essentially no significant quantity of thetherapeutic composition after administration of the single unit-dose orthe prescribed number of multiple unit-doses.

It is also an object of the invention to provide the novel and improvedcombination of a device for intranasal administration and a formulationfor lorazepam that meet the requirements for FDA approval.

Yet another object of the invention is to provide such novel lorazepamcompositions for intranasal administration in a relatively small andinexpensive, manually operated, self-contained hand-held disposabledevice that retains essentially no significant quantity of thetherapeutic composition after administration of the one or moreunit-doses as prescribed.

A further object of the invention is to provide a comprehensive methodfor providing a novel therapeutic composition for intranasaladministration that contains lorazepam in a form that exhibits the samepharmacological activity as lorazepam compositions that are approved fororal, IM and/or IV administration, the intranasal composition beingavailable for delivery in highly accurate and reproducible predeterminedunit-doses leaving essentially no significant quantity of thetherapeutic composition after administration of the prescribed number ofunit-doses.

As used herein, the term “essentially no significant quantity of thetherapeutic composition” means none, or a trace amount, or an amountthat is so small that it cannot be recovered for a subsequent unintendeduse or abuse after the prescribed use.

As used herein, the term “spray” means the liquid composition expressedfrom the device under pressure in the form of an aerosol, a fine mist,liquid droplets, a fine stream, and combinations of two or more of theabove forms. It will be understood that the precise form of thecomposition is dependent upon the viscosity and other physicalproperties of the composition and the manner in which the manual orother force is applied to the device to discharge the liquidcomposition. A heterogenous spray is acceptable so long as the sprayedvolume is effectively adsorbed by the nasal mucosa.

As used herein, “lorazepam” means lorazepam and its activepharmaceutically acceptable derivatives and metabolites.

SUMMARY OF THE INVENTION

The improved lorazepam composition for intranasal spray administrationis prepared by dissolving lorazepam in polyethylene glycol having anaverage molecular weight of 400, [“PEG 400”] and diluting the solutionwith propylene glycol to a final composition of about 20% PEG 400 and80% propylene glycol 2 by volume.

The invention further comprehends the intranasal administration of thelorazepam composition in the form of a spray in a unit-dose of apredetermined therapeutic volume, where substantially all of thepredetermined volume of the composition is sprayed from delivery meanswithin a specified narrow range of accuracy, while leaving essentiallyno significant quantity of the therapeutic composition in the applicatorfrom the unit-dose as administered. The dose is administered principallyin the form of liquid droplets, that may be accompanied by a minorproportion of an atomized mist or an aerosol. Application to the nasalmucosa of a subject requiring treatment is consistent with the currenttherapeutic use of lorazepam for treatment of anxiety-related disorders,and especially useful when acute administration is indicated. Suchindications include sedation of agitated and/or demented patientspre-operative surgical/dental sedation and administration to children.

The lorazepam compositions administered in accordance with the methodand system of the invention exhibit systemic pharmacological effectsfollowing absorption from the nasal mucosa. As will be shown below, thenovel pharmaceutical composition provide the lorazepam in a form that isreadily absorbable by the nasal mucosa without damaging or irritatingthe mucosa, or producing an allergic, or other unacceptable reaction inthe recipient.

The lorazepam compounds for use in the practice of the inventioncomprise a pharmacologically acceptable carrier that can be nasallyadministered with safety over the entire reasonably foreseeable range ofprescribed users of the composition. It has been found that the additionof water to the composition reduces the stability of the lorazepam. Itis therefore preferred that the liquid composition be non-aqueous.Compatible organic solvents ar preferred.

In one preferred embodiment, the lorazepam composition includes minorproportion of an artificial sweetener. The purpose of the artificialsweetener is to counteract or mask the otherwise bitter taste that thesubject can experience if the composition reaches the taste buds. Flavorextracts can also be included in the composition, either in addition toor in place of an artificial sweetener to mask the after taste of thelorazepam composition. The composition preferably has a shelf life inthe chosen delivery system of at least six months, and most preferablygreater than two years. Optionally, the composition can include one ormore preservatives of the type approved for use in pharmaceuticalcompositions. The preservative is preferably an anti-oxidant. Onepreservative that has been found particularly suitable is butylatehydroxytolune, which can be added at the rate of 0.1 mg/mL.

The lorazepam composition of the invention is also compatible with thedelivery system. The lorazepam compositions for use in the invention areformulated to deliver the dose within the foreseeable temperature rangesof exposure, e.g., without becoming too viscous to be administered inthe proper form by the device, or crystallizing at lower temperatures;and without exceeding the internal pressure limits of the deliverysystem at higher temperatures.

The predetermined therapeutic volume of the pharmaceutical compositioncontained in the unit dose is delimited by several parameters, includingthe capability of the nasal passage to receive and absorb the volumetricquantity of spray; and the solubility of the particular lorazepam in thephysiologically and pharmacologically acceptable carrier liquid at theconcentration required to achieve the desired effect. The relativesafety of administering a given predetermined quantity of lorazepam toclasses of patients for anxiety-related disorders or for sedation, whosebody weight, age, general health, use of other medications may varywidely and can be determined by methods well known in the art.

Dispensing devices meeting the above criteria and technicalspecifications have been provided in accordance with the invention bymodifying commercially available devices, such as those sold by Pfeifferof America of Princeton, N.J. and Valois of America, Inc. of Greenwich,Conn. When modified as described below, such devices have the capabilityof consistently delivering a predetermined volumetric amount of a liquidcomposition intranasally via a unit-dose dispenser that is manuallyoperable by the patient requiring such intranasal drug administration.These manually operable devices are designed for delivery of a singleunit-dose, after which there is essentially significant quantity of thetherapeutic composition remaining in the device. The device canthereafter be discarded without concern that others may abuse thecontrolled substance.

Commercial spray devices can be provided with enough pharmacologicallyactive composition to administer one predetermined unit-dose or twounit-doses (“bi-dose”), each with a high degree of accuracy andreproducibility for the device and among a plurality of suchcommercially manufactured and filled devices.

In accordance with the invention, the orifice of a commercial sprayapplicator was enlarged and the swirl chamber is retained in order toproduce a spray that is principally in the form of liquid droplets thatcoat the nares. A minor proportion of the product may be in the form ofa mist or aerosol. The size of the orifice is optimized in relation tothe viscosity of the lorazepam composition.

Devices that are suitable for use in the practice of the invention arefabricated from a variety of polymeric materials, and can also includeglass or polymer containers for the liquid lorazepam composition andmetal components, preferably of stainless steel, that form elements ofthe delivery system. Such devices are compact, relatively inexpensiveand can be discarded after the prescribed use. In a preferredembodiment, the container and its sealing means are sterilizable; mostpreferably, the entire device is constructed from materials that can besterilized.

The preparation of the lorazepam composition and its aseptic fillinginto containers and the assembly of the filled containers in the spraydevices must be completed under aseptic conditions since the lorazepamcannot withstand terminal sterilization without decomposition. Spraydevices can be sterilized before filing, along with the intendedpackaging, employing methods and technology that are well known in theart.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features and other advantages of the present invention, inaddition to those mentioned above, will become apparent to those skilledin the art from the following detailed description and in conjunctionwith the accompanying drawings, in which:

FIG. 1 is a graphic representation of the concentration of lorazepam inblood plasma versus time for IV, IM and IN doses; and

FIG. 2 is a graphic representation of the data of FIG. 1 over a longertime period.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

A suitable liquid composition for use in a spray device for intranasaladministration includes a solvent in which the desired concentration oflorazepam can be attained to provide the desired unit-dose in a totalsprayed liquid volume that can be delivered by the device andaccommodated and absorbed by the subject's nasal mucosa. Lorazepam isinsoluble in water. A commercially available injectable compositionapproved by the FDA and sold by Wyeth Laboratories under the brand nameAtivan®, includes 2 mg of lorazepam in 0.18 mL of polyethylene glycol400 in propylene glycol with 2.0% benzyl alcohol as a preservative. Thiscomposition was not acceptable for intranasal spray administrationbecause benzyl alcohol is irritating to the mucosa.

A suitable composition for use in the invention was prepared as follows.

Lorazepam was formulated in a liquid composition for use in the practiceof the invention. Since lorazepam is insoluble in water, the lorazepamwas dissolved in polyethylene glycol having an average molecular weightof about 400 (“PEG400”), and the solution diluted with propylene glycol.In order to provide for shelf-life stability over a period of up tosix-months under typical conditions, a preservative can be added. In apreferred embodiment, an artificial sweeter is also dissolved in thecomposition. The final composition was as follows: lorazepam 10.0 mgpolyethylene glycol 400 0.18 mL propylene glycol 0.809 mL butylatehydroxytolune 0.1 mg saccharin (powder) 1.0 mg

The lorazepam is preferably prepared in the form of a single orunit-dose nasal spray for intranasal administration by a precisiondosage manually-activated pump. Each 1 ml of nasal spray solution ispreferably formulated to contain 10 mg lorazepam. In a preferreddelivery system, each actuation of the nasal spray pump delivers 0.1 mlof this 10 mg/ml hm solution constituting a 1 mg dose. A smaller dose ofthe lorazepam HCl can be administered to children.

As will be understood by those familiar with the art, dosage forms atlower concentrations of lorazepam can be prepared for administrationbased upon the patient's lower body weight, as in the case of childrenor adults of substantially smaller size. The nasal spray solution has apH in the range of from about 3 to about 7, with a pH of about 5 beingpreferred.

The lorazepam composition was placed in containers adapted for use withmodified Pfeiffer dispensers identified by model/part numbers as52020/BSK 7482. The intranasal applicators of the prior art are modifiedby increasing the size of the discharge orifice in nose piece to about0.07 mm from about 0.05 mm in diameter (which is typical for an aqueoussolution), i.e., a 40% increase in diameter. This increase is necessaryto accommodate the higher viscosity of the composition of the invention.The swirl chamber of the prior art precision spray dispenser can beretained. The applicator components are sterilized by methods well knownin the art. As will be understood by those of ordinary skill in the art,other changes in the design and/or construction of the spray dispensercan be made to accommodate and discharge the more viscous composition ofthe invention.

The lorazepam nasal spray applicators are preferably stored attemperatures in the range of 2°-8° C. (36°-48° F.) and are protectedfrom light to provide for maximum shelf life. If the applicator body isnot transparent, visual inspection of the drug product for signs ofdeterioration is not possible and attention to the expiration date andstorage conditions is important. The optional inclusion of apreservative will serve to extend the shelf life, as will storage underrefrigeration. In the last case, the products and dispenser should bebrought to room temperature before administration. Any expired productis discarded in the appropriate manner.

A formulation of lorazepam for intranasal administration was prepared asdescribed above under aseptic conditions in the form of a liquidcomposition at a concentration of 1.0 mg of lorazepam in 0.1 mL. Thecomposition was used to fill the required number of single-dose, meteredsprayers commercially produced and sold by Pfeiffer of America, Inc.,each of which sprayers first having been modified as described above.The filling of the containers and their assembly is completed underaseptic conditions since the lorazepam composition cannot withstand theheat of sterilization.

Each subject received a single spray in each nostril for a total of 2.0mg. A 2.0 mg dose is preferred as being within common, safe and labeleddoses prescribed. Commercially available lorazepam was purchased for IMand IV administration. The product was Ativan® Injection for parentaladministration sold by Wyeth Laboratories, (a Wyeth-Ayerst Company.)Each mL of Ativan® Injection is formulated with 2 mg of lorazepam in0.18 mL PEG400 in propylene glycol with 2.0% benzyl alcohol as apreservative. The IV doses were diluted according to the labelinstructions by adding one mL of water.

Each of the applicators was weighed prior to use and after use.Qualified medical personnel took the respective applicators to subjectsin a clinical setting; one dose was administered up each nostril, afterwhich the applicator was recovered for weighing. Each subject used twoPfeiffer unit dose spray devices, both of which were discarded followingthe post-use weighing. The IV doses were administered throughantecubital veins on the arm opposite to the arm from which samples weretaken, injecting the solution over about five minutes. Syringes wereweighed before and after administration. Further details of theprotocol, and the results of these studies of the methods and system ofthe invention and the comparative prior art method follow.

Unit-Dose:

A statistical comparison of dose 1 and dose 2 for the Pfeiffer unit dosedelivery system was done using a paired t-test. Analysis of the data fornormally functioning devices indicated that the difference between themean sprays of the two applications using the Pfeiffer device was notstatistically significant. (This analysis excluded data from one of thedevices that malfunctioned.)

Investigational Methods

A clinical study was undertaken for the purposes of (1) to assessing theabsolute bioavailability of lorazepam by comparing the pharmacokineticsof 2.0 mg lorazepam administered by intranasal (IN) and intravenous (IV)routes; and (2) to compare pharmacokinetic parameters via INadministration to intramuscular (IM) and intravenous administration.This was undertaken as a single-dose, open-label, three-way crossover,randomized, pilot bioavailability study of lorazepam comparingintranasal administration in healthy human volunteers.

Twelve healthy non-smoking subjects (six male and six female) betweenthe ages of 18 and 35 years were initially selected for this inpatientstudy. One subject left the study and one subject received delayeddoses. Study participants were selected based on inclusion/exclusioncriteria, history and physical exam, laboratory tests, and othercustomary procedures.

The subjects were within ±20% of ideal body weight and no history ofallergies, acute or chronic nasal symptoms, significant nasal surgery orabnormalities were reported.

Eleven of the twelve subjects completed the study according to theprotocol. Each of the subjects received 3 doses of 2 mg of lorazepam onthree separate occasions. No clinically significant protocol violationsoccurred during this study. The inclusion criteria mentioned abstinencefrom prescription and non-prescription drugs prior to and during thestudy, and any medications taken in the 14 days before the study andduring the study were noted. Subjects abstained from alcoholic andcaffeine-containing beverages for 48 hours before the dosing period andduring the study.

Clinical Trials

Study Drug Formulation

Lorazepam for intranasal administration was supplied by the Universityof Kentucky College of Pharmacy. Lorazepam for intravenousadministration (“IV”) was supplied as Ativan® 1 mg/mL for subjects 1, 3,8, and 9 on the first day and for subjects 2, 4, 5, 6, and 7 on thesecond study day. Lorazepam for intramuscular administration (“IM”) wassupplied as Ativan® 2 mg/mL for subjects 2, 4, 5, 6 and 7 on first studyday and for subjects 1, 3, 8 and 9 on the second study day. Free basecontent was 1.77 mg or 88.7% of stated lorazepam strength (frommolecular weights: 321.8-36.46=285.34, 285.34/321.8=88.7%) To summarize,the dosages for each of the three routes of administration were asfollows:

Treatment A: 2.0 mg intravenous lorazepam;

Treatment B: 2.0 mg intramuscular lorazepam; and

Treatment C: 2.0 mg intranasal lorazepam solution

Study Drug Administration

Drug administration occurred at approximately 0800 hours followingovernight fasting. Subjects were allowed up to 360 mL of juice or softdrink one hour before each dose, but were not allowed to eat for onehour after their dose.

Safety Measures

Weight, blood pressure, and pulse were measured prior to dosing and atthe end of the study. Blood pressure and pulse rate were measured withthe subjects seated in an upright position before any correspondingblood sample was collected. Blood pressure and pulse rate were measuredand recorded on the same arm throughout the study at 0 (pre-dose) and 30minutes, 1, 2, 4, 8, and 16 hours.

The three treatments were separated by one-week washout period. Thesubject (#02) whose doses were delayed received the final dose withinone month of the first dose, was dosed with the other subjects duringtheir first and third periods and received the final treatment two weekslater. She was dosed in the treatment order to which she was randomized.

Clinical Adverse Events

Spontaneously reported adverse events were recorded by the subjectsthroughout the study; adverse events were also elicited by nondirectedinterviews.

Sample Collection and Handling

Blood samples for the three treatments were collected from each subjectaccording to the following schedule: 0 (pre-dose), 5, 15, 30 and 45minutes, and 1, 2, 3, 4, 8, 12, 18, 24 and 36 hours following lorazepamadministration. The beginning of the IV administration was consideredtime zero. After collection, the blood was centrifuged in a refrigeratedcentrifuge at 4° C. to separate the plasma and the cells, and the plasmawas transferred to polypropylene tubes. The plasma was stored atapproximately −70° C. at the study site until shipped to an independentanalytical service. The plasma was maintained frozen during shipping andupon arrival at the remote analytical facility, the samples were storedat approximately −20° C. until analyzed.

Bioanalytical Methods

LC/MS/MS Assay for lorazepam

The sample analysis using an LC/MS/MS assay was performed by anindependent service in accordance with established protocols. Theanalytic range for the lorazepam method was 0.10 ng to 25.00 ng/mL using1.0 mL of human plasma. Concentrations less than 1.10 ng/mL werereported as below quantitation limit (BQL). Samples with concentrationsgreater than 25 ng/mL were reanalyzed using a dilution so that theassayed concentration was within the range of 0.10 ng to 25.00 ng/mL.

Pharmacokinetic Methods

Plasma concentration versus time date for lorazepam were analyzed usingnoncompartmental pharmacokinetic methods. Pharmacokinetic parameterswere determined using standard noncompartmental methods with log-linearleast square regression analysis to determine the elimination rateconstants (WinNonlin, Pharsight Corp., Palo Alto, Calif.). The areasunder the concentration versus time curves from time zero to infinity(AUC_(0-∞)) were calculated by a combination of the linear andlogarithmic trapezoidal rules,-with extrapolation to infinity bydividing the last measurable serum concentration by the elimination rateconstant (λ_(Z)) (Proost, 1985). Values for the maximum concentration(C_(max)) and time to

C_(max) (T_(max)) were determined by visual inspection of concentrationversus time data for each subject. The elimination half-life wasdetermined from 0.693/λ_(Z). The absolute bioavailability (F) for the INand IM dosage forms, assuming equal 2 mg doses, was determined byF=AUC_(IN,0-∞)/AUC_(IV,0-∞) for the IN dose andF=AUC_(IM,0-∞)/AUC_(IV,0-/∞) for the IM dose. Clearance (CL for IV andCL/F for IN and IM doses) was determined by dividing the dose byAUC_(0-∞). Volume of distribution at steady state and for elimination(V_(SS) and V_(Z)) were determined by moment curves (Gibaldi andPerrier, 1982). TABLE 1 Mean (CV as a %) pharmacokinetic parametersfollowing administration of 2 mg intravenous (IV infusion over 5 min),intranasal (IN) and intramuscular (IM) lorazepam doses in 11 healthyvolunteers. Parameter 2 mg IV 2 mg IM 2 mg IN T_(max) (hrs*) 0.1 3.0 0.5(0.083 to 1.017) (0.5 to 8.017) (0.25 to 2) C_(max) (ng/mL) 47.57 (57.8)22.58 (28.9) 21.38 (24.3) t_(1/2) (hr)  16.6 (27.3)  17.4 (38.1)  18.5(28.3) AUC₀₋₄ (ng · hr/mL) 386.8 (19.4) 372.8 (16.4) 288.0 (25.4)AUC_(0-∞) 500.8 (30.8) 506.2 (33.7) 393.5 (38.0) (ng · hr/mL) CL or CL/F(L/hr)  4.3 (27.0)  4.3 (28.5)  5.7 (31.8) V_(ss) (L)  93.2 (11.9) — —V_(z) or V_(z)/F (L)  97.8 (15.2)  99.2 (10.8) 140.1 (16.8) F (%) assume100% 100.9 (10.2)  77.7 (11.1)*median and range given for T_(max)

Table 1 is a summary of pharmacokinetic data for the three doses.Absorption of lorazepam following IN administration was rapid asindicated by the fact that concentrations were detected in all subjectswithin five minutes after the IN administration. The median T_(max)values were 30 minutes and three hours for the IN and IM doses,respectively. On average, 0.1091 g (CV 5.6%, n=21) was dispensed fromthe individual spray pumps as determined by the difference in the pre-and post-weights. (This data excludes one malfuctioning device of the 22devices used in this study.) The mean plasma concentration versus timecurve profiles for the IV, IM and IN doses are shown in FIG. 1. Plasmaconcentrations were still detectable 36 hours after administration.

FIGS. 1 and 2 are plots of the mean (n=11) plasma lorazepamconcentration versus time graphs following three treatments: (A) 2.0 mglorazepam by five minutes IV infusion, (B) 2.0 mg lorazepam IN dose and(C) 2.0 mg lorazepam IM dose. FIG. 1 shows the results over the periodfollowing administration; FIG. 2 is the same data for the 36 hoursfollowing administration.

Safety Results

Results of the clinical measurement of vital signs and body weight examswere recorded and nasal exams were performed. A review of this datafailed to reveal any clinically significant safety concerns. There wereno serious adverse events and no subjects were discontinued due toadverse effects. Subjects commented that they experienced a mild badtaste immediately after the IN dose. Any safety concerns associated withIN are similar to those associated with IV administration.

Detailed nasal examination demonstrated no pathology of the naso-pharynxafter single administration of the lorazepam formulations.

Pharmacokinetic Results

The plasma lorazepam concentrations and actual collection times for eachof the 11 subjects was tabulated and plasma concentration-time curvesfor each of the 11 subjects were prepared. The mean concentration-timecurves of FIGS. 1 and 2 are representative for most subjects (mean datatabulation). FIG. 1 is a plot of the mean (n=11) lorazepam concentrationversus time graphs following IV, IM and IN doses of 2 mg lorazepamduring the 4 hours after dose; FIG. 2 is the same data plotted for 36hours after the dose.

Noncompartmental pharmacokinetic analysis was used to evaluate theplasma concentration versus time curves of lorazepam following single2.0 mg doses of lorazepam by intravenous (IV), intramuscular (IM), andintranasal (IN) routes. Individual plasma lorazepam concentration versustime profiles for all subjects were recorded; number of time points usedto estimate the elimination rate constant were also recorded; and acomplete listing of individual and mean pharmacokinetic parameters forall 11 subjects was recorded. Table 1 is a summary of the descriptivestatistics for lorazepam pharmacokinetic parameters.

Rapid absorption of lorazepam was observed after the IV and IN doses.The T_(max) values were approximately 9 and 18 minutes, on average, forthe IM and IN doses, respectively. The mean T_(max) for the IV infusionwas not the first blood sample after the end of the infusion for tworeasons. The peak concentration after the IV dose in one subject was notat the first blood sample after the end of the IV infusion, but at thenext time point. In the case of Subject 4, acquiring the blood sampleimmediately following the IV infusion was delayed resulting in the meanT_(max) being affected. As expected, the lorazepam C_(max) and AUCs weresignificantly higher after IM and IV administration compared to INadministration. Mean plasma half-lives and clearance after correctingfor bioavailability, were similar for all three treatments.

The arithmetic mean value of absolute bioavailability of lorazepam (11subjects) for the IN formulation is 78%. The plasma levels werecomparable to those of the IM dose.

From the above, it will be understood that a novel composition andmethod is provided for the safe and controlled intra-nasaladministration of precise doses of lorazepam in accordance with amedically prescribed regimen.

1. A pharmaceutical composition for intranasal administration to amammal in the form of a controlled unit-dose liquid spray to produce apharmacologically induced sedative-anxiolytic physiological response inthe mammal, the composition comprising: lorazepam; a physiologicallyacceptable non-aqueous, organic liquid solvent-carrier for thelorazepam; and a preservative, wherein the liquid composition forming aspray when discharged from a manually actuated spray device.
 2. Thecomposition of claim 1, wherein the solvent-carrier is selected from thegroup consisting of polyethylene glycol, propylene glycol, and mixturesthereof.
 3. The sprayable composition of claim 1, wherein thesolvent-carrier constitutes a minor proportion of the composition. 4.The composition of claim 2, wherein the solvent carrier comprisespolyethylene glycol having an average molecular weight of about
 400. 5.The composition of claim 2, wherein the polyethylene glycol constitutesfrom about 15% to about 25% by volume and the propylene glycol fromabout 75% to about 85% by volume of the liquid composition.
 6. Thecomposition of claim 5, wherein the polyethylene glycol constitutesabout 20% by volume and the polpylene glycol about 80% by volume of theliquid composition.
 7. The composition of claim 6, wherein thesolvent-carrier is polyethylene glycol having an average molecularweight of about
 400. 8. The composition of claim 6, wherein thelorazepam is present at a concentration of 1.0 mg/0.1 mL of liquid. 9.The composition of claim 1 which further includes an additive selectedfrom the group consisting of preservatives, artificial sweeteners,flavors, and combinations thereof.
 10. A sprayable liquid pharmaceuticalcomposition for the controlled intranasal administration in the form ofat least one unit-dose to a mammal for the purpose of producing asedative-anxiolytic response in the mammal, the composition comprising:lorazepam; a physiologically acceptable non-aqueous solvent for thelorazepam; and a preservative, wherein the lorazepam is present in theliquid composition at a concentration of about 1.0 mg/0.1 mL.
 11. Thecomposition of claim 10 which further includes a physiologicallyacceptable liquid solute for the lorazepam solvent.
 12. The compositionof claim 11, wherein the solute for the lorazepam solvent is propyleneglycol water.
 13. The composition of claim 12, wherein the lorazepamsolvent is polyethylene glycol having a number average molecular weightof about
 400. 14. The composition of claim 13, wherein the ratio ofpolyethylene glycol to propylene glycol is about four-to-one.
 15. Thecomposition of claim 13, wherein the solvent constitutes about 80% byvolume and the propylene glycol about 18% by volume.
 16. The compositionof claim 10 which further includes an artificial sweetener selected fromthe group consisting of saccharin and aspartame.
 17. The composition ofclaim 16, wherein the sweetener is saccharin.
 18. The composition ofclaim 10 which further includes a preservative.
 19. The composition ofclaim 18, wherein the preservative is butglated hydroxytokrene.
 20. Amethod of treating a mammal exhibiting symptoms of anxiety-relateddisorders, said mammal requiring treatment, the method comprising thesteps of: a. providing a controlled dose intranasal spray deliverydevice; b. filling the delivery device with a sprayable liquidcomposition, the liquid composition comprising: lorazepam, aphysiologically acceptable solvent-carrier for the lorazepam; and c.administering a predetermined measured dose of the liquidlorazepam—containing composition intranasally to the mammal requiringtreatment by spraying the liquid composition droplets from the deliverydevice into at least one of the mammal's nostrils.
 21. The method ofclaim 20, wherein the dose is administered by manually activating thedelivery device.
 22. The method of claim 20, wherein the predetermineddose is administered by spraying the lorazepam-containing compositionfirst in one nostril and then in the other.
 23. The method of claim 20,wherein the mammal is an adult human and the predetermined dose is twomg. of lorazepam.
 24. The method of claim 20, wherein the sprayableliquid composition is prepared by dissolving lorazepam in an organicsolvent selected from the group consisting of polyethylene glycol 400,propylene glycol, and mixtures thereof, and adding the lorazepamsolution to the delivery device under aseptic conditions.
 25. The methodof claim 20 which includes the further step of sterilizing the deliverydevice before addition of the liquid composition.